Some recent clinical findings promise significant advances in the treatment of atherosclerotic heart disease and stroke. The cyclooxygenase inhibitor sulfinpyrazone, given orally to 1,475 patients after a myocardial infarction, reduced mortality by 50% in the first year of treatment. In similar studies, the more potent cyclooxygenase inhibitor aspirin was ineffective. In 585 patients with threatened stroke, however, aspirin reduced mortality by 48% in males whereas sulfinpyrazone was inactive. The reasons for such differences in therapeutic effectiveness will be investigated in this proposal. We have shown that the protective effects of cyclooxygenase inhibitors can be duplicated in an experimental animal model. These drugs significantly reduce platelet aggregation and atherosclerotic plaque development in rabbits fed an atherogenic diet for a period of 3 months. A series of 15 anti-inflammatory drugs will be tested to define the biochemical and pharmacological properties which determine effectiveness in this system. Studies will include measurement of drug levels in blood and tissues including brain, lung, heart and vascular tissue, inhibition of platelet aggregation in vivo and platelet conversion of arachidonic acid to thromboxanes. Particular attention will be paid to changes in metabolism of vascular tissues in vivo, including synthesis of prostacyclin in vascular endothelium and prostaglandins associated with inflammatory responses in areas of active plaque development. Differential sensitivity of cyclooxygenases in brain, lung, heart and vascular tissue to the drugs will be measured. Studies will be supplemented with gross morphological and scanning E.M. observations of major blood vessels. These comparative studies will be used to establish a profile of those characteristics which enhance anti-atherogenicity and those which detract from it. The experiments will provide some of the basic biological data which is needed for design and interpretation of further studies with these drugs in the therapy of myocardial infarction and stroke.